H. pylori chronically infects more than 50% of the world's population and is a significant cause of gastritis, peptic ulcer disease and gastric cancer Within the gastric niche, the bacterium interacts with host cells and elaborates a number of virulence factors that influence disease etiology. Chief among these pathogenic determinants is the cytotoxin-associated gene A product, CagA, a protein that is injected into host cells via a Type IV secretion system. Once inside host cells, CagA is tyrosine phosphorylated by host cell Src/Lyn kinases and subsequently alters host cell physiology via interaction with Src homology region 2, phosphatase 2 (SHP-2) and disruption of multiple signaling pathways. These changes are believed to be central to development of H. pylori-induced disease since epidemiological data indicate that persons infected with CagA-positive strains of H. pylori are significantly more likely to develop severe forms of gastric disease than individuals who harbor CagA-negative isolates. Additionally, the C-terminal portion of CagA is polymorphic specifically in the region that undergoes tyrosine phosphorylation. Epidemiologic evidence and in vitro tissue culture studies indicate that this natural CagA polymorphism may be a crucial determinant for the predisposition of infected individuals to develop gastric cancer. However, all of the cell culture studies that have linked CagA polymorphism to enhanced H. pylori modulation of host cell pathways have either used nonisogenic strains of H. pylori or relied upon transfection models. Interpretation of these study results is complicated by the fact that H. pylori shows a remarkably high degree of strain variation, and transfection studies likely do not accurately mimic bacterial delivery of CagA during the course of a natural infection. Our lab has designed and constructed isogenic strains of H. pylori that differ only in the C-terminal phosphorylation domain of the CagA protein and herein we propose to use these novel strains to aid our long term goal of understanding H. pylori pathogenesis by defining the role of CagA polymorphism in host cell changes and disease development using a short-term gastric cancer small animal model.